A Study in Participants With Non-cirrhotic NASH With Fibrosis (COSMOS)

A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Pharmacodynamics of AZD4831 (Mitiperstat) in Participants With Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) With Fibrosis

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Participants will be in the trial for up to 24 weeks, including a screening period lasting up to 8 weeks, a 12-week treatment period, and a 4-week safety follow-up period

Participants are not expected to directly benefit from treatment during this trial. Participants will help researchers learn more about and how to develop AZD4831 to treat NASH.

Study Overview

• Status: Completed
• Conditions: Non-Cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
• Intervention / Treatment: Other: Placebo; Drug: AZD4831

Detailed Description

A randomized, double blind, placebo-controlled, parallel-group, multicenter study including a maximum of approximately 90 randomized adult participants with biopsy-proven non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis (NAS ≥ 4, fibrosis stages F1, F2, F3). The study will be conducted at approximately 48 sites across approximately 9 countries.

During screening, the participants will be checked for eligibility and enrolled in the study. Following a 8-week screening period, approximately 90 participants will be randomized in a 1:1 ratio to once daily dosing of AZD4831 or placebo. All participants will be treated once daily with AZD4831 or placebo for 12 weeks. The safety, tolerability, and pharmacodynamics will be evaluated at 12 weeks. This is the first clinical study to test AZD4831 in participants with non-cirrhotic NASH with fibrosis.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1056ABJ
    • Research Site
  • Caba, Argentina, C1119ACN
    • Research Site
  • Caba, Argentina, C1426
    • Research Site
  • Ciudad de Buenos Aires, Argentina, 1280
    • Research Site
  • Mar del Plata, Argentina, 7600
    • Research Site
  • Pilar, Argentina, 1664
    • Research Site
  • Ramos Mejía, Argentina, B1704ETD
    • Research Site
• Denmark
  • Aarhus N, Denmark, 8200
    • Research Site
  • Esbjerg, Denmark, 6700
    • Research Site
  • Koge, Denmark, 4600
    • Research Site
  • København NV, Denmark, 2400
    • Research Site
  • København Ø, Denmark, 2100
    • Research Site
• Italy
  • Catania, Italy, 95100
    • Research Site
  • Foggia, Italy, 71100
    • Research Site
  • Milan, Italy, 20122
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Roma, Italy, 00168
    • Research Site
  • Roma, Italy, 00128
    • Research Site
  • Rozzano, Italy, 20089
    • Research Site
  • San Giovanni Rotondo, Italy, 71013
    • Research Site
  • Torino, Italy, 10126
    • Research Site
• Mexico
  • Boca del Rio, Mexico, 94299
    • Research Site
  • Ciudad de Mexico, Mexico, 06700
    • Research Site
  • Cuauhtémoc, Mexico, 06700
    • Research Site
  • Guadalajara, Mexico, 44670
    • Research Site
  • Guadalajara, Mexico, 44210
    • Research Site
  • Guadalajara, Mexico, 44340
    • Research Site
  • Mexico City, Mexico, 03330
    • Research Site
  • Mexico D.F., Mexico, 014080
    • Research Site
  • Monterrey, Mexico, 64460
    • Research Site
  • Monterrey, Mexico, 64710
    • Research Site
  • Monterrey, Mexico, 64000
    • Research Site
  • México, Mexico, 03300
    • Research Site
• Norway
  • Gjøvik, Norway, 2819
    • Research Site
  • Grålum, Norway, 1714
    • Research Site
  • Lørenskog, Norway, N-1478
    • Research Site
  • Oslo, Norway, 0456
    • Research Site
  • Tromsø, Norway, N-9038
    • Research Site
• Portugal
  • Lisboa, Portugal, 1250-189
    • Research Site
• Spain
  • La Coruña, Spain, 15006
    • Research Site
  • Lérida, Spain, 25198
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
  • Málaga, Spain, 29010
    • Research Site
  • Pozuelo de Alarcon, Spain, 28223
    • Research Site
  • Santander, Spain, 39008
    • Research Site
  • Valencia, Spain, 46014
    • Research Site
• Sweden
  • Linköping, Sweden, 581 85
    • Research Site
  • Uppsala, Sweden, 751 85
    • Research Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Research Site
    • Tucson, Arizona, United States, 85712
      • Research Site
  • California
    • Chula Vista, California, United States, 91911
      • Research Site
    • Montclair, California, United States, 91763
      • Research Site
    • Orange, California, United States, 92868
      • Research Site
    • Redondo Beach, California, United States, 90277
      • Research Site
    • Stanford, California, United States, 94305
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Research Site
    • Lakeland, Florida, United States, 33813
      • Research Site
    • Lakeland, Florida, United States, 33803
      • Research Site
    • Miami, Florida, United States, 33135
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Research Site
  • New York
    • Yonkers, New York, United States, 10701
      • Research Site
  • North Carolina
    • Morehead City, North Carolina, United States, 28557
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75230
      • Research Site
    • Houston, Texas, United States, 77090
      • Research Site
    • San Antonio, Texas, United States, 78229
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participant must be ≥ 18 to ≤ 75 years of age at the time of signing the informed consent.

2. Histological confirmed NASH per Clinical Research Network (CRN) criteria as diagnosed by liver biopsy (within 12 months prior screening, participants without historical biopsy should be willing to undergo a liver biopsy at screening) fulfilling all of the following criteria:

   • NAS ≥ 4 with a score of ≥ 1 for each component: steatosis, lobular inflammation and ballooning
   • Presence of fibrosis F1, F2-F3
3. One increased serum ALT measurement (ALT > ULN) at screening, and historical local serum ALT level (> ULN [41 U/L for men and 31 U/L for women] but < 300 U/L) on ≥ 1 occasion in the 6 months prior to screening.

Exclusion Criteria:

1. Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral, or autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; hemochromatosis; alpha 1 antitrypsin deficiency; Wilson's disease).
2. History of excessive alcohol consumption, defined as an average weekly intake of > 21 drinks/week for males or > 14 drinks/week for females. One drink is equivalent to 14 g alcohol.
3. Recent (within 3 months of randomization) use of drugs approved for weight loss (eg, orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as those drugs used off-label.
4. High dose vitamin E (> 400 IU) unless on a stable dose within 6 months of screening.
5. Recent (within 6 months of screening) use of therapies associated with development of NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines).
6. Recent (within 6 months of screening) use of obeticholic acid or other therapy under investigation for NASH.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo
Experimental: AZD4831	Drug: AZD4831; AZD4831

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative to Baseline Alanine Aminotransferase (ALT)	ALT at 12 weeks relative to baseline. ALT is measured in Units per litre (U/L)	Measurements on Baseline, Week 2, Week 4, Week 8, Week 12 and Week 16. Change reported from Baseline to Week 12.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative to Baseline Pro-C3	Pro-C3 at 12 weeks relative to baseline. Pro-C3 is measured in nanograms per milliliter (ng/mL).	Measurements on Baseline, Week 4 and Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Adverse Events/Serious Adverse Events (AEs/SAEs) and abnormal clinical test results	Maculopapular rash grade 3, Vital signs and clinical chemistry	12 weeks
Number of participants with Adverse Events/Serious Adverse Events (AEs/SAEs) and abnormal laboratory test results	Haematology, urinalysis, electrocardiogram (ECG) assessments and eGFR	12 weeks

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• D6581C00001-Redacted_SAP
• D6581C00001_Redacted_CSP
• d6581C00001-Redacted_CSR_Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2022
• Primary Completion (Actual): April 4, 2024
• Study Completion (Actual): April 4, 2024

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: November 25, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Actual): July 9, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: NASH; Non-Cirrhotic; Steatohepatitis
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Fibrosis; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: D6581C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No